The Metabolic Syndrome defines a constellation of conditions, often co-existing in an individual, that together greatly enhance the risk of developing diabetes and coronary artery disease. Two of the major components of the Metabolic Syndrome are hypertension and obesity. Since there has been a marked increase in the incidence of these conditions within the western population, it is becoming increasingly important to understand how these risk factors contribute to the onset of the costly and debilitating diseases of diabetes and heart disease. Angiotensin II (Ang II) is a peptide hormone whose overproduction is one of the most common causes of hypertension. While the effects of Ang II on blood pressure are primarily mediated through its actions on the vascular bed, the hormone also acts in a variety of other tissues. It is in these tissues, such as liver, that Ang II activates the NF-:B transcription factor, an event that is central to the development of insulin resistance. Numerous studies have shown that activation of NF-:B serves as a mechanism for inhibitory cross-talk with insulin signal transduction. We recently described a novel intracellular signaling pathway that mediates Ang II- dependent activation of NF-:B in hepatocytes, and involves the concerted efforts of three principal proteins, CARMA3, Bcl10, and MALT1. Thus, we hypothesize that this signaling pathway may be critical to the development of Ang II-dependent insulin resistance. Interestingly, free fatty acids (FFAs), which are elevated in the plasma of obese individuals, also activate hepatic NF-:B and thereby contribute to insulin resistance. Since the actions of Ang II and FFAs share a number of features, we further hypothesize that FFAs utilize the same CARMA3/Bcl10/MALT1 pathway to activate NF-:B and induce a state of insulin resistance. The goal of this grant proposal is to further test the role of CARMA3, Bcl10, and MALT1 in blocking insulin signaling in liver, and in promoting the physiologic state of insulin resistance in the setting of chronic obesity or Ang II overproduction. We will accomplish this goal through four specific aims that (1) specifically test whether FFA induction of NF-:B does in fact depend on the CARMA3/Bcl10/MALT1 pathway, (2) test the role of the CARMA3/Bcl10/MALT1 pathway in mediating cross-talk with hepatic insulin signaling pathways, (3) test the role of the CARMA3, Bcl10, and MALT1 proteins in mediating Ang II- and obesity-dependent insulin resistance in a mouse model, and (4) test if genetically deleting CARMA3 will restore a normal insulin-sensitive phenotype in a strain of mice that are prone to developing insulin resistance because of defective Leptin signaling. PUBLIC HEALTH RELEVANCE: The onset of hypertension- or obesity-dependent insulin resistance is a first major step toward the development of type 2 diabetes, a condition that is typically irreversible. It is therefore critical that we further explore the molecular mechanisms that underlie insulin resistance, with the goal of developing novel strategies for blocking the progression to diabetes. This proposal will explore a novel signaling pathway that may underlie some of the most common causes of insulin resistance and may thereby provide new molecular targets for therapeutic intervention.